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Aunon-Calles D.,Seprox Biotech | Giordano E.,IMDEA Madrid Institute for Advanced Studies | Bohnenberger S.,Harlan Cytotest Cell Research Harlan CCR GmbH | Visioli F.,IMDEA Madrid Institute for Advanced Studies
Pharmacological Research | Year: 2013

Hydroxytyrosol (HT) is an olive-derived phenol endowed with several biological activities, some of which demonstrated in humans. Indeed, the European Food Safety Authority (EFSA) allows the health claim that HT (≥5 mg/d) "protects LDL particles from oxidative damage". In terms of safety, HT has been investigated as the predominant part of raw olive mill waste water extracts that have been granted the Generally Recognized as Safe (GRAS) status. Also, a long-term toxicological study of HT proposed a NOAEL of 500 mg/kg/d. As several HT-containing supplements and functional foods are entering the market, we sought to investigate the genotoxic and mutagenic potential of HT, using well-established in vitro models, i.e. the chromosomal aberration assay and the Ames test (by using the Salmonella typhimurium TA 100, TA98, TA1535, and TA1537 strains and Escherichia coli WP2(pKM101)), with and without S9-induced metabolic activation). Even though we cannot rule out that prolonged exposure to HT and its metabolites might have untoward effects, the results of this study indicate that HT is non-genotoxic and non-mutagenic at concentrations that far exceed those attainable after intake. © 2013 Elsevier Ltd. All rights reserved. Source


Bohnenberger S.,Harlan Cytotest Cell Research Harlan CCR GmbH | Bruce S.W.,BioReliance | Kunkelmann T.,Harlan Cytotest Cell Research Harlan CCR GmbH | Pant K.,BioReliance | And 4 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

This catalogue is a display of Syrian hamster embryo (SHE) cell colony photos representative of the cell transformation assay (CTA) carried out at pH 6.7. It is intended as a visual aid for the identification and the scoring of cell colonies in the conduct of the assay.A proper training from experienced personnel together with the protocol reported in this issue and the present photo catalogue will support method transfer and consistency in the assay results. © 2011 Elsevier B.V. Source


Sasaki K.,Hatano Research Institute | Bohnenberger S.,Harlan Cytotest Cell Research Harlan CCR GmbH | Hayashi K.,Hatano Research Institute | Kunkelmann T.,Harlan Cytotest Cell Research Harlan CCR GmbH | And 7 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

This catalogue is a display of focus photos representative of the BALB/c 3T3 cell transformation assay (CTA). It is intended as a visual aid for the identification and the scoring of foci in the conduct of the assay.A proper training from experienced personnel together with the protocol reported in this issue and the present photo catalogue will support method transfer and consistency in the assay results. © 2012 Elsevier B.V. Source


Maire M.-A.,French National Center for Scientific Research | Pant K.,BioReliance | Phrakonkham P.,European Commission - Joint Research Center Ispra | Poth A.,Harlan Cytotest Cell Research Harlan CCR GmbH | And 8 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

The Syrian hamster embryo (SHE) cell transformation assay (CTA) is a short-term in vitro assay recommended as an alternative method for testing the carcinogenic potential of chemicals. SHE cells are " normal" cells since they are diploid, genetically stable, non-tumourigenic, and have metabolic capabilities for the activation of some classes of carcinogens. The CTA, first developed in the 1960s by Berwald and Sachs (1963,1964) [3,4], is based on the change of the phenotypic feature of cell colonies expressing the first steps of the conversion of normal to neoplastic-like cells with oncogenic properties. Pienta et al. (1977) [22] developed a protocol using cryopreserved cells to enhance practicality of the assay and limit sources of variability. Several variants of the assay are currently in use, which mainly differ by the pH at which the assay is performed. We present here the common version of the SHE pH 6.7 CTA and SHE pH 7.0 CTA protocols used in the ECVAM (European Centre for the Validation of Alternative Methods) prevalidation study on CTA reported in this issue. It is recommended that this protocol, in combination with the photo catalogues presented in this issue, should be used in the future and serve as a basis for the development of the OECD test guideline. © 2011 Elsevier B.V. Source


Tanaka N.,Hatano Research Institute | Bohnenberger S.,Harlan Cytotest Cell Research Harlan CCR GmbH | Kunkelmann T.,Harlan Cytotest Cell Research Harlan CCR GmbH | Munaro B.,European Commission - Joint Research Center Ispra | And 8 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

The cell transformation assays (CTAs) have attracted attention within the field of alternative methods due to their potential to reduce the number of animal experiments in the field of carcinogenicity. The CTA using BALB/c 3T3 cells has proved to be able to respond to chemical carcinogens by inducing morphologically transformed foci. Although a considerable amount of data on the performance of the assay has been collected, a formal evaluation focusing particularly on reproducibility, and a standardised protocol were considered important. Therefore the European Centre for the Validation of Alternative Methods (ECVAM) decided to coordinate a prevalidation study of the BALB/c 3T3 CTA. Three different laboratories from Japan and Europe participated. In the study the following modules were assessed stepwise: test definition (Module 1) consisted of the standardisation of the protocol, the selection of the cell lineage, and the preparation of a photo catalogue on the transformed foci. The within-laboratory reproducibility (Module 2) and the transferability (Module 3) were assessed using non-coded and coded 3-methylcholanthrene. Then, five coded chemicals were tested for the assessment of between-laboratory reproducibility (Module 4). All three laboratories obtained positive results with benzo[a]pyrene, phenanthrene and o-toluidine HCl. 2-Acetylaminofluorene was positive in two laboratories and equivocal in one laboratory. Anthracene was negative in all three laboratories. The chemicals except phenanthrene, which is classified by IARC (http://monographs.iarc.fr) as group 3 " not classifiable as to its carcinogenicity to human" , were correctly predicted as carcinogens. Further studies on phenanthrene will clarify this discrepancy. Thus, although only a few chemicals were tested, it can be seen that the predictive capacity of the BALB/c 3T3 CTA is satisfactory.On the basis of the outcome of this study, an improved protocol, incorporating some changes related to data interpretation, has been developed. It is recommended that this protocol be used in the future to provide more data that may confirm the robustness of this protocol and the performance of the assay itself. During the study it became clear that selecting the most appropriate concentrations for the transformation assay is crucial. © 2012 Elsevier B.V. Source

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